Patent GB-817138-A (GB)
Title: Substituted benzimidazoles
IPC: C07D401/12
Filed: 1956-04-13
Abstract: The invention comprises compounds of the formula <FORM:0817138/IV (b)/1> (wherein X, X1 and Y are hydrogen or halogen atoms or alkyl or alkoxy radicals of 1 to 4 carbon atoms, Alk is an alkylene group of 1 to 4 carbon atoms, R is hydrogen or an alkyl radical of 1 to 4 carbon atoms and -NR1R11 is a dialkylamino radical wherein the alkyl groups have 1 to 4 carbon atoms or is a saturated, nitrogen containing 5- or 6-membered heterocyclic radical), their acid-addition salts and quaternary ammonium derivatives and their preparation by the following methods: (1) for compounds wherein Alk is an ethylene radical, by reduction of the appropriate N-(2-benzimidaz-olylmethyl)-N-phenylglycinamide with lithium aluminium hydride in an anhydrous, inert solvent, e.g. tetrahydrofuran or dioxan or mixtures thereof, 1:2-dimethoxyethane or N-ethylmorpholine, preferably with heating; (2) condensing the appropriate 2-halomethylbenz-imidazole with the appropriate diamine or an acid addition salt thereof in the presence of sodium iodide catalyst and a polar, anhydrous solvent, e.g. methanol or ethanol or mixtures thereof, isopropanol, acetonitrile or a mixture of ethanol and acetone, preferably at 50 DEG  to 100 DEG  C.; (c) condensing a compound of the general formula <FORM:0817138/IV (b)/2> with a compound of the formula <FORM:0817138/IV (b)/3> or an acid-addition salt thereof, preferably in a high-boiling solvent, e.g. ethylene glycol, at 200 DEG  C.; and (d) for compounds wherein R is alkyl, by condensing 1-alkyl-2-halomethyl-benzimidazole with an alkali-metal derivative of the appropriate alkylene diamine, which may be prepared from the alkylene diamine and the metal amide in a hydrocarbon solvent at 100 DEG  C. or from an alkyl or aryl lithium.  Examples describe the preparation of compounds of the general formula I wherein X, X1, Y, R, Alk and -NR1R11 have the following values, by the methods indicated: <FORM:0817138/IV (b)/4> Some of the above products are described in the form of their hydrochlorides, hydrobromides and picrates and the preparation of N-[5 (6)-chloro-2-benzimidazolylmethyl] - N - phenyl - 2-aminoethyl - trimethylammonium chloride hydrochloride is also described.  Starting materials.-Compounds of the general formula <FORM:0817138/IV (b)/5> are prepared by condensing the appropriate 2-chloromethylbenzimidazole with a (lower alkyl)-N-phenyl-glycinate in the presence of sodium iodide catalyst and a polar anhydrous solvent, e.g. ethanol or methanol, and condensing the lower alkyl N-(2-benzimidazolylmethyl)-N-phenylglycinate so obtained with an amine NHR1R11.  Examples describe the reaction of 2-chloromethylbenzimidazole with ethyl N-phenylglycinate to form ethyl N-(2-benzimidazolylmethyl-N-phenylglycinate which with dimethylamine gives the corresponding dimethylamide, and the preparation, by a similar method, of N - (2 - benzimidazolylmethyl) - N - phenylglycine piperamide. Compounds of the general formula II are prepared by acid hydrolysis, e.g. with concentrated sulphuric acid at below 60 DEG C., of the corresponding nitriles, themselves prepared by cyanomethylation of an alkylene diamine of the formula <FORM:0817138/IV (b)/6> by means of formaldehyde bisulphite and an alkali metal cyanide. Examples describe the preparation of N-cyanomethyl-N-phenyl-N1:N1-dimethylethylenediamine (hydrochloride and picrate described) and the corresponding amide by these methods. 1-n-Butyl-2-chloromethylbenzimidazole is prepared by the action of thionyl chloride on the corresponding hydroxy compound, which is prepared from 2-hydroxymethylbenzimidazole and n-butyl bromide.